What role do cannabinoids have in modern medicine as gastrointestinal anti-inflammatory drugs?

KEYWORDS:

• Inflammatory bowel disease
• endocannabinoid system
• cannabinoids
• cannabis

1. Introduction

Inflammatory bowel disease (IBD) is a type of relapsing and remitting disease which is associated with disturbance of immune cell hemostasis, also in the intestinal mucosa. There are three main types of IBD: Crohn’s disease (CD), ulcerative colitis (UC), and unclassified IBD (IBD-U). IBD is becoming an increasingly common problem because its incidence and prevalence have increased significantly over the past few decades. Several methods are currently being used to control symptoms and improve patients’ quality of life, but new, more effective treatment options are still being sought [1].

Cannabis sativa, also known as marijuana, has been cultivated and used forcenturies for recreational and medicinal purposes. Cannabis plant contains at least 60 cannabinoids and several other compounds such as terpenoids, flavonoids, or alkaloids [2]. The main psychoactive substance in C. sativa is Δ9-tetrahydrocannabinol (THC) but it also contains pharmacologically relevant cannabidiol (CBD), tetrahydrocannabivarin, cannabichromene, and cannabigerol. Cannabis extracts have been used throughout centuries for a variety of diseases due to their anti-inflammatory, antiemetic, antidiarrheal, and analgesic properties. In addition to plant-derived compounds, there are two other classes of cannabinoids – synthetic (e.g. WIN55212-2) and endogenous such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG) [3]. Overall, cannabinoid-based drugs are used mainly in chronic diseases where standard treatment does not have positive effects [4]. Cannabinoids can be administered in many ways, including oral, sublingual, inhaled, or local.

Cannabinoids affect the cells by interacting with cannabinoid receptors coupled with G protein (‘classical’ – CB1 and CB2 and ‘non-classical’ – e.g. GPRs and TRPs), which are part of the endocannabinoid system (ECS). In general, ECS, apart from receptors, includes their endogenous ligands as well as enzymes synthesizing (diacylglycerol lipase, DAGL, and N-acylphosphatidyl ethanolaminophospholipase D, NAPE-PLD) and degrading (fatty acid amide hydrolase, FAAH, and monoacylglycerol lipase, MAGL) cannabinoid ligands.

2. Endocannabinoid system in a pre-clinical setting

Maintenance of intestinal homeostasis is possible through ECS. It is important to note that both centrally- and peripherally mediated effects are essential to maintain gut in good health [5].

Studies using animal models of dextran sulfate sodium (DSS)- or trinitrobenzene sulfonic acid (TNBS)-induced colitis have shown increased expression of ECS components, namely CB1, CB2 and AEA, thus suggesting the involvement of cannabinoid signaling in inflammation [6,7]. In addition, the FAAH expression, which is responsible for the degradation of AEA, is lowered in the early stages of colitis [8]. Furthermore, several studies have observed changes in the expression of ECS elements in the human inflamed tissue compared to non-inflamed colons. The data are summarized in Table 1.

Table 1. Expression of ECS and ECS-related elements in human colon in Crohn’s disease (CD) and ulcerative colitis (UC) compared to non-inflamed tissue [9,10]

ECS elements	CD	UC
AEA	↓	↓
CB1	↑ or -	↑
CB2	- (PCR) or ↑ (immunohistochemistry)	-
FAAH	↑	↑
NAPE-PLD	↓	↓
OEA	↑	↑
PEA	-	-

– (no changes in expression), ↑ (increase in expression), ↓ (decrease in expression)

AEA, anandamide; CB1, cannabinoid receptor type 1; CB2, cannabinoid receptor type 2; FAAH, fatty acid amide hydrolase; NAPE-PLD, N-acylphosphatidyl ethanolaminophospholipase D; OEA, oleoylethanolamide; PEA, palmitoylethanolamide

Concurrently, it was showed that the activation of cannabinoid receptors protects against colitis, and inhibition of degrading enzymes (FAAH or MAGL) relieves inflammation [5] (Table 2). Moreover, cannabinoids reduce the degree of visceral sensitivity by activating CB1 and CB2 [11]. In contrast, a selective CB1 antagonist rimonabant intensifies hyperalgesia caused by colitis, confirming the involvement of ECS in inflammatory hyperalgesia [12].

Table 2. The role of cannabinoids in preclinical models of colitis [13]

Cannabinoid	Effects
AM841 (CB1 and CB2 agonist)	Anti-inflammatory effect, reduction in gastric emptying and intestinal transit
HU210 (nonselective cannabinoid receptor agonist)	Amelioration of inflamed colon in colitis, protective effect on the intestinal barrier function
ACEA (CB1 agonist)	Attenuation of inflammation in OM and DSS-induced colitis models
WIN 55,212–2 (CB1 agonist)	Reduction in diarrhea
AM1241 (CB2 agonist)	Reduction in murine colitis
JWH-133 (CB2 agonist)	Reduction in murine colitis
O-1966 (CB2 agonist)	Increased percentage of T regulatory cells, decrease in pro-inflammatory cytokines
O-1602	Protection against experimentally induced colitis and inhibition of neutrophil recruitment
URB597 (FAAH inhibitor)	Significant reduction in macroscopic alterations of the colon
Cannabichromene	Reduction of inflammation-induced hypermotility in vivo, altered mRNA expression of TRPA1
Cannabigerol	Attenuation of murine colitis, reduction in nitric oxide production in macrophages
Cannabis sativa extract with high content of cannabidiol	Reduction in intestinal hypermotility, attenuation of motility in DNBS model of inflammation
Tetrahydrocannabivarin	Inhibition of nitrate production in macrophages
THC and cannabinol	Attenuation of serum IgE, IL-2, IL-4, IL-5 and IL-13 mRNA level

Research has revealed a strong link between the microbiome and ECS. Gut microbiota were found to modulate CB1, FAAH, and MAGL expression in the mouse colon [14]. In addition, Lactobacillus acidophilus was shown to induce CB2 receptor expression in the intestinal epithelial cells and rodent intestinal mucosa [15]. On the other hand, the growth of the Akkermansia municiphila strain, which has beneficial effects in the mouse model of colitis, is associated with the action of CB1 antagonists. Namely, the blockade of CB1 has significantly increased the relative abundance of these bacteria [16]. Moreover, it has been shown that AEA stimulates the myeloperoxidase activity in the intestine, which is a marker of intestinal inflammation and is also involved in the inflammatory process caused by Clostridium difficile toxin A [17]. To sum up, since intestinal microbiota has important metabolic and host-protective functions and plays a key role in the etiopathogenesis of IBD, its interaction with cannabinoids could be employed in IBD treatment [18].

3. Cannabinoids as anti-inflammatory drugs

Current IBD therapy is based on anti-inflammatory agents, corticosteroids as well as biological agents such as anti-TNF, vedolizumab, or ustekinumab, which are used in severe forms of IBD. However, treatment with biological agents may involve side effects; moreover, the success rate of IBD therapies ranges only from 40% to 60%. New, low-toxicity therapeutic options are thus being sought to support the pharmacological treatment of IBD and – when combined with conventional anti-IBD drugs – to increase its effectiveness.

IBD patients often use cannabis to combat the disease symptoms such as abdominal pain, nausea, diarrhea and to improve their mood and consequently their quality of life. Due to legal restrictions, it is difficult to estimate the number of IBD patients who use this therapeutic option, but several studies indicate that between 6.8% and 17.6% of IBD patients actively take cannabis [19]. Similarly, no reliable data is available to demonstrate the effectiveness of cannabis in IBD. In one of many studies, patients with CD took cannabis in the form of prepared cigarettes in the dose of 50 g dry processed plant per month. They used marijuana whenever they felt pain, taking up to three inhalations each time from prepared cigarettes to avoid psychiatric side effects [20]. Patients reported a significant improvement in general well-being, ability to work, and pain reduction. They were able to gain weight to a normal body mass index. The only randomized study [21] which assessed the effects of marijuana on CD showed induction of clinical remission after 8 weeks of treatment, which allowed discontinuation of steroid treatment while using cannabis. However, there were no differences in biochemical parameters, including hemoglobin and CRP levels between cannabis and placebo groups. Importantly, cannabis has reduced abdominal pain and improved quality of life. It should be noted that all patients reported deterioration of health within 2 weeks after stopping cannabis use [21].

Many scientists are currently looking for substances among the ingredients of cannabis that can be used as anti-IBD agents. Studies have confirmed the importance of CBD as a promising drug in the treatment of IBD and preclinical colitis models [22,23]. CBD normalizes in vivo induced hypermotility and can inhibit FAAH, showing anti-inflammatory effects in the intestine. Moreover, CBD reduces the severity of intestinal inflammation by controlling the neuroimmune axis [24]. In a randomized placebo-controlled study, Naftali et al. [25] evaluated the effect of CBD on CD. They showed that the administration of CBD was safe, but had no beneficial effects. The lack of any therapeutic effect in this case may have resulted from a low dose of CBD or a small number of patients in the study, so further studies are recommended [25].

4. Side effects of cannabis and cannabinoid use

Storr et al. reported that 36% of IBD patients who were afraid of using cannabis were worried about its side effects [26]. Long-term use of cannabis raises concerns about the development of addiction. Lal et al. showed that almost a third of the patients with IBD reported significant side effects, from euphoria and increased awareness to dry mouth, palpitations, anxiety, and memory loss [27]. On the other hand, Wang et al. reported the occurrence of almost 5,000 adverse events as complications, while approximately 97% were not considered as serious [28].

Concurrently, the safety of cannabis and cannabinoid use versus the intestines is questionable. For example, for many years CBD was considered to have anticonvulsant properties, but due to a lack of sufficient research and reports, it was not used for this purpose. It is currently estimated that around one-third of epilepsy patients do not respond well to commonly used antiepileptic drugs [29]. Recently, a randomized, controlled, double-blind study was conducted for the first time to assess the effect of CBD on seizure control in patients with Lennox-Gastaut syndrome (childhood seizure disorder associated with encephalopathy). It was found that CBD caused a 43.9% reduction in drop seizures. However, one of the most common complications was diarrhea and decreased appetite, which occurred in 86% of patients in the CBD group. In this case, cannabis plant ingredients can help treat epilepsy, but their long-term use contributes to gastrointestinal disorders [30].

5. Expert opinion

IBD is becoming a common problem in many countries around the world. In 2017, there were 6.8 million new cases of IBD worldwide, and the incidence of IBD increased significantly in the years 1990–2017, which can be a social and economic burden in the coming years. Currently, plant-derived drugs are being developed, which may be an alternative treatment method or an important element complementing standard therapy [31].

The ECS is involved in the intestinal inflammatory process, therefore, it becomes a potential therapeutic target in the treatment of IBD. Despite reports confirming the potential positive effects of components of Cannabis sativa on IBD, additional studies are required to determine the mechanisms of action of (endo)cannabinoids in inflammatory diseases. Moreover, extensive clinical trials are needed to determine the efficacy, doses, best administration methods and side effects of long-term use of (endo)cannabinoids. In reference to the latter, all we know so far is that short-term cannabis use leads to dizziness or hallucinations, while its long-term use causes mental disorders and impaired liver and bile duct function [32]. However, questions like whether the synthetic cannabinoid agonists are safer than phytocannabinoids or what their off target side effects remain unanswered. With cost-effectiveness already better understood for natural ligands, these issues need to be addressed in the future.

In conclusion, there is a potential in cannabinoid use in IBD. Currently, the main objective is to create effective medicinal products based on cannabinoids that do not cause serious adverse effects.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One referee declares that they act as a consultant for STERO, a company that develops CBD for clinical use. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

The authors are supported by the Medical University of Lodz, Poland (via grant number #503/1-156-04/503-11-001).